RESUMEN
OBJECTIVE: Impaired glucose tolerance (IGT) is common among obese adolescents. The aim of the present study was to investigate the association between glucose tolerance and intramyocellular, intra-abdominal and liver fat in adolescents presenting with early-onset severe obesity. DESIGN AND METHODS: We studied 21 adolescents (mean age 13.5 years, range 11.5-15.9 years) referred to secondary care due to severe obesity (relative weight for height > +60% or body mass index > 98th percentile for age and sex, before the age of 10 years) and their eight non-obese siblings (mean age 14.4 years, range 11.8-16.7 years). All subjects underwent oral glucose tolerance tests, followed by magnetic resonance spectroscopy (MRS) to measure the intramyocellular fat content in mainly oxidative soleus and mainly glycolytic tibialis anterior muscles. MRS was also used to measure liver fat. Abdominal fat (subcutaneous, intraperitoneal and retroperitoneal) was measured using MR imaging. RESULTS: Compared with their non-obese siblings, the obese adolescents had increased fat deposition in all anatomic locations studied. Eight obese adolescents had IGT, and they also had increased intramyocellular fat in the soleus (P=0.03) and increased intraperitoneal fat (P=0.04) compared with obese subjects with normal glucose tolerance (NGT). In contrast, no significant difference was seen between obese adolescents with NGT and IGT in liver fat (P=0.9) or intramyocellular fat in the tibialis anterior (P=0.13). In logistic regression analysis, increased soleus intramyocellular fat and intraperitoneal fat were significant predictors of IGT. CONCLUSIONS: IGT in obese adolescents is associated with increased intramyocellular and intraperitoneal fat rather than liver fat.
Asunto(s)
Grasa Abdominal/metabolismo , Hígado Graso/sangre , Intolerancia a la Glucosa/sangre , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/metabolismo , Obesidad/sangre , Adolescente , Factores de Edad , Composición Corporal/fisiología , Niño , Estudios Transversales , Hígado Graso/complicaciones , Hígado Graso/diagnóstico , Femenino , Intolerancia a la Glucosa/complicaciones , Humanos , Masculino , Obesidad/complicaciones , Obesidad/diagnósticoRESUMEN
RATIONALE AND OBJECTIVES: To compare liver perfusion parameters obtained by using an extravascular contrast agent and a blood-pool agent. MATERIALS AND METHODS: Fifteen rabbits were imaged with a continuous 40-second single-slice computed tomography acquisition after a bolus injection of contrast agent (physiologic bolus duration 4-5 seconds, extravascular iohexol, n = 7; experimental nanoparticulated blood-pool agent WIN8883, n = 8). Time-density curves were generated for the aorta, portal vein, and liver. From the curves, arterial, portal, and total blood flows and hepatic perfusion index (HPI, arterial-to-total perfusion ratio) were determined by using two commonly applied fundamentally different analyzing methods: the single-compartment model and the peak gradient (PG) method. Also, the gamma variate fitting method was used. RESULTS: By using the single-compartment model, the obtained HPI and total blood flow were 0.14 +/- 0.04 and 2.29 +/- 0.40 (mL/min/mL(tissue)) for WIN8883, and 0.15 +/- 0.06 (P = .54) and 4.60 +/- 1.14 (mL/min/mL(tissue)) (P = .0002) for iohexol, respectively. With the PG, HPI and total blood flow were 0.15 +/- 0.08 and 1.27 +/- 0.24 (mL/min/mL(tissue)) for WIN8883, and 0.20 +/- 0.06 (P = .12) and 2.11 +/- 0.25 (mL/min/mL(tissue)) (P = .00002) for iohexol, respectively. With the blood pool agent, similar contrast enhancement to the conventional agent was achieved with about 36% reduced dosage of iodine per body weight (mg I/kg). CONCLUSIONS: HPI was found to be quite insensitive to different contrast agent types and analyzing methods. However, the arterial, portal and total liver blood flow values strongly depend on contrast agent type and modeling method.
Asunto(s)
Medios de Contraste , Diatrizoato/análogos & derivados , Yohexol , Circulación Hepática , Tomografía Computarizada por Rayos X , Animales , Volumen Sanguíneo , Hígado/diagnóstico por imagen , ConejosRESUMEN
OBJECTIVE: We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity. RESEARCH DESIGN AND METHODS: A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 +/- 0.3 vs. 14.4 +/- 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations. RESULTS: Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-gamma and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group. CONCLUSIONS: Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.
Asunto(s)
Tejido Adiposo/metabolismo , Ceramidas/metabolismo , Hígado Graso/metabolismo , Tejido Adiposo/citología , Adolescente , Adulto , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Recuento de Células Sanguíneas , Tamaño de la Célula , HDL-Colesterol/sangre , Citocinas/genética , Ayuno , Hígado Graso/complicaciones , Hígado Graso/genética , Hígado Graso/patología , Femenino , Regulación de la Expresión Génica , Salud , Humanos , Inmunohistoquímica , Inflamación/complicaciones , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Insulina/sangre , Macrófagos/citología , Persona de Mediana Edad , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Inhibidor 1 de Activador Plasminogénico/genética , ARN Mensajero/genética , Triglicéridos/sangreRESUMEN
BACKGROUND: Highly active antiretroviral therapy (HAART) is associated with loss of subcutaneous fat (lipoatrophy) presumably due to mitochondrial toxicity of nucleoside reverse transcriptase inhibitors. In vitro, uridine abrogates thymidine analogue-induced toxicity in adipocytes. METHODS: A total of 20 patients with HAART-associated lipoatrophy were randomized to receive either a dietary uridine supplement (36 g three times a day for 10 consecutive days/month) or placebo, for 3 months. Body composition was measured using dual energy X-ray absorptiometry, magnetic resonance imaging and proton spectroscopy. Data are mean +/- standard error of mean. RESULTS: The mean increases in limb fat (880 +/- 140 versus 230 +/- 270 g; P < 0.05), intra-abdominal fat (210 +/- 80 versus -80 +/- 70 cm3; P < 0.05) and total body fat (1920 +/- 240 versus 240 +/- 520 g; P < 0.01) were significantly greater in the uridine than in the placebo group. Within the uridine group, the changes from baseline to 3 months were statistically significant in total limb fat (P < 0.001), intra-abdominal fat (P < 0.05) and total body fat (P < 0.001). The proportion of limb fat to total fat increased from 18% to 25% (P < 0.05) in the uridine group. Liver fat content and lean body mass remained unchanged in both groups. High-density lipoprotein-cholesterol concentrations decreased in the uridine and increased in the placebo group, whereas fasting serum insulin concentrations did not change. Uridine supplementation was well tolerated and the virological effect of HAART was not affected. CONCLUSION: Uridine supplementation significantly and predominantly increased subcutaneous fat mass in lipoatrophic HIV-infected patients during unchanged HAART.
Asunto(s)
Antirretrovirales/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Suplementos Dietéticos , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Síndrome de Lipodistrofia Asociada a VIH/tratamiento farmacológico , Uridina/uso terapéutico , Absorciometría de Fotón , Administración Oral , Composición Corporal/efectos de los fármacos , Distribución de la Grasa Corporal , Método Doble Ciego , Esquema de Medicación , Femenino , Infecciones por VIH/virología , Síndrome de Lipodistrofia Asociada a VIH/inducido químicamente , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Análisis Espectral , Grasa Subcutánea/efectos de los fármacos , Resultado del Tratamiento , Uridina/administración & dosificaciónRESUMEN
UNLABELLED: We determined whether insulin therapy changes liver fat content (LFAT) or hepatic insulin sensitivity in type 2 diabetes. Fourteen patients with type 2 diabetes (age 51+/-2 yr, body mass index 33.1+/-1.4 kg/m2) treated with metformin alone received additional basal insulin for 7 mo. Liver fat (proton magnetic resonance spectroscopy), fat distribution (MRI), fat-free and fat mass, and whole body and hepatic insulin sensitivity (6-h euglycemic hyperinsulinemic clamp combined with infusion of [3-(3)H]glucose) were measured. The insulin dose averaged 75+/-10 IU/day (0.69+/-0.08 IU/kg, range 24-132 IU/day). Glycosylated hemoglobin A1c (Hb A1c) decreased from 8.9+/-0.3 to 7.4+/-0.2% (P<0.001). Whole body insulin sensitivity increased from 2.21+/-0.38 to 3.08+/-0.40 mg/kg fat-free mass (FFM).min (P<0.05). This improvement could be attributed to enhanced suppression of hepatic glucose production (HGP) by insulin (HGP 1.04+/-0.28 vs. 0.21+/-0.19 mg/kg FFM.min, P<0.01). The percent suppression of HGP by insulin increased from 72+/-8 to 105+/-11% (P<0.01). LFAT decreased from 17+/-3 to 14+/-3% (P<0.05). The change in LFAT was significantly correlated with that in hepatic insulin sensitivity (r=0.56, P<0.05). Body weight increased by 3.0+/-1.1 kg (P<0.05). Of this, 83% was due to an increase in fat-free mass (P<0.01). Fat distribution and serum adiponectin concentrations remained unchanged while serum free fatty acids decreased significantly. CONCLUSIONS: insulin therapy improves hepatic insulin sensitivity and slightly but significantly reduces liver fat content, independent of serum adiponectin.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Resistencia a la Insulina , Insulina/uso terapéutico , Lípidos/análisis , Hígado/química , Hígado/metabolismo , Alanina Transaminasa/sangre , Metabolismo Basal , Diabetes Mellitus Tipo 2/metabolismo , Combinación de Medicamentos , Ácidos Grasos no Esterificados/análisis , Glucosa/metabolismo , Humanos , Metformina/uso terapéutico , Persona de Mediana Edad , Oxidación-ReducciónRESUMEN
OBJECTIVE: To determine whether acquired obesity or accompanying metabolic changes such as adiponectin deficiency, insulin resistance, dyslipidemia, or visceral fat are associated, independent of genetic influences, with endothelial dysfunction by studying young adult monozygotic (MZ) twin pairs discordant for obesity. RESEARCH METHODS AND PROCEDURES: Nine obesity-discordant (intra-pair difference in BMI, 3.8 to 10.1 kg/m(2)) and nine concordant (0 to 2.3 kg/m(2)) 24- to 27-year-old MZ twin pairs were identified from a population-based FinnTwin16-sample. Endothelial function was measured by blood flow responses to intrabrachial infusions of an endothelium-dependent (acetylcholine) and an endothelium-independent (sodium nitroprusside) vasodilator. Whole body insulin sensitivity was measured using the euglycemic insulin clamp technique, and forearm and body composition were measured with magnetic resonance imaging and DXA. In addition, serum levels of adiponectin, high-sensitivity C-reactive protein, and lipids were determined. RESULTS: The heavier co-twins of the discordant pairs had significantly lower whole body insulin sensitivity than the leaner co-twins. Blood flows/muscle volume during infusions of acetylcholine and sodium nitroprusside were not altered by obesity. However, intra-pair differences in serum adiponectin, intra-abdominal fat, and C-reactive protein were significantly correlated with those in endothelial function. Only the relationship between intra-pair differences in adiponectin and endothelial function persisted in multiple linear regression analysis. Obesity-concordant co-twins had comparable insulin sensitivity and endothelial function. DISCUSSION: In young adult MZ twins discordant for obesity, acquired adiponectin deficiency rather than obesity per se is an independent correlate of endothelial dysfunction.
Asunto(s)
Enfermedades en Gemelos/fisiopatología , Endotelio Vascular/fisiopatología , Obesidad/fisiopatología , Gemelos Monocigóticos , Acetilcolina/farmacología , Adiponectina/sangre , Adulto , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea/fisiología , Composición Corporal/fisiología , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Enfermedades en Gemelos/genética , Relación Dosis-Respuesta a Droga , Femenino , Antebrazo/irrigación sanguínea , Frecuencia Cardíaca/fisiología , Humanos , Resistencia a la Insulina/fisiología , Masculino , Nitroprusiato/farmacología , Obesidad/sangre , Obesidad/genética , Análisis de Regresión , Triglicéridos/sangre , Vasodilatadores/farmacologíaRESUMEN
Proton magnetic resonance spectroscopy ((1)H MRS) has revealed biochemical alterations in various psychiatric disorders. Changes in brain metabolites may be caused not only by the disease's progression or response to treatment, but also by physiological variability. The aim of this study was to use (1)H MRS to assess the effects of specific short-term physiological states on major metabolites. Eight healthy women underwent (1)H MRS at the beginning and end of a 40-h period of sleep deprivation. The ratios of N-acetyl-aspartate (NAA), total creatine (tCr), and choline-containing compounds (Cho) to water (H(2)O) were determined from the occipital cortex during both baseline and photic stimulation conditions. During sleep deprivation, NAA/H(2)O decreased by 7% and Cho/H(2)O by 12%. Photic stimulation had no effect on the measured metabolites in the alert state, but in the sleep-deprived state the level of Cho/H(2)O increased during neuronal activation. The results suggest that NAA/H(2)O and Cho/H(2)O may depend on the state of alertness.
Asunto(s)
Espectroscopía de Resonancia Magnética , Lóbulo Occipital/metabolismo , Lóbulo Occipital/fisiopatología , Protones , Privación de Sueño/fisiopatología , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Colina/metabolismo , Creatina/metabolismo , Electroencefalografía , Metabolismo Energético/fisiología , Femenino , Humanos , Estimulación Luminosa/métodos , Factores de Tiempo , Vigilia/fisiologíaRESUMEN
RATIONALE AND OBJECTIVES: The goal was to improve informativeness in the determination of liver perfusion with a clinically available iodinated computed tomography (CT) contrast agent by developing open multicompartmental modeling. MATERIALS AND METHODS: Contrast-enhanced functional CT (fCT) examinations were conducted with temporal resolutions of 200-500 msec to 6 New Zealand White rabbits. First, we applied conventional open two-compartment model for the determination of arterial and portal blood flows (FA and FP), blood and interstitial volume fractions (fb and fi), and capillary permeability-surface area product (PS) of liver parenchyma. Then, we improved the modeling of vascular physiology by developing three- and open four-compartment models. For comparison, conventional single-compartment model was applied. We determined FA and FP also by using the peak-gradient method. RESULTS: Conventional two-compartment model yielded identical fittings with single-compartment model and does not provide unique solutions for fb and fi. The presented open four-compartment model provided FA and FP values of 0.40 +/- 0.19 and 1.99 +/- 0.57 mL/min/mL (tissue), fb and fi values of 0.30 +/- 0.05 and 0.19 +/- 0.04 mL/mL (tissue), and PS values of 4.0 +/- 1.7 mL/min/mL (tissue). FA and FP are in a good agreement with those derived by using the peak-gradient method. CONCLUSIONS: With the use of clinical extracellular iodinated CT contrast agent, the presented open four-compartment model provided physiological arterial and portal blood flow values and is also a potential tool in the assessment of blood and interstitial volume fractions and capillary permeability-surface area product. Moreover, the model requires neither measurements from hepatic vein or from other organs nor visual determination of arterial or portal phase.
Asunto(s)
Velocidad del Flujo Sanguíneo/fisiología , Circulación Hepática/fisiología , Hígado/irrigación sanguínea , Hígado/diagnóstico por imagen , Modelos Cardiovasculares , Sistema Porta/diagnóstico por imagen , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Animales , Volumen Sanguíneo/fisiología , Determinación del Volumen Sanguíneo/métodos , Simulación por Computador , Medios de Contraste , Conejos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND AND PURPOSE: In MR spectroscopic imaging (MRSI), the volume-selection profiles of metabolites differ from each other. These differences cause variations in metabolite intensities, which are particularly prominent when the hippocampi are evaluated. We hypothesize that the errors arising from these effects cause notable artifact when temporal lobe epilepsy (TLE) is lateralized with MRSI. METHODS: We examined a metabolite phantom, control subjects, and patients with TLE by using MRSI. We calculated the error arising from the different volume-selection profiles of metabolites in vitro and evaluated this correction in the examination of the control subjects and in the lateralization of epilepsy in the patients. RESULTS: Without a correction, a considerable error in the metabolite content existed, even deep inside the spectroscopic volume of interest. The result was false asymmetry (P < .008) in the hippocampi of control subjects. Among the 11 patients, TLE was correctly lateralized in three only after the correction was made, and in one, TLE was incorrectly lateralized. CONCLUSION: The volume-selection profiles of N-acetylaspartate, choline, and creatine differ enough to cause a significant error, even in the metabolite ratios, when patients with TLE are examined with MRSI. We propose a simple phantom method to correct for this error without a need to modify the pulse sequence.
Asunto(s)
Epilepsia del Lóbulo Temporal/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Fat accumulation in the liver has been shown to be closely correlated with hepatic insulin resistance and features of insulin resistance, even independent of body weight. The reason for interindividual variation in liver fat content is unknown. Cross-sectional data suggest that dietary fat content may influence liver fat, but this possibility has not been directly tested in humans. DESIGN AND METHODS: Liver fat (proton spectroscopy), intraabdominal and sc fat (magnetic resonance imaging), and markers of insulin sensitivity (insulin, free fatty acids, and lipids) were determined in 10 normal, obese women (age, 43 +/- 5 yr, mean +/- sd; body mass index, 33 +/- 4 kg/m2; range, 27-38 kg/m2) at baseline and after two 2-wk isocaloric periods containing either 16% (low-fat diet) or 56% (high-fat diet) of total energy as fat. RESULTS: Liver fat at baseline averaged 10 +/- 7%. It decreased by 20 +/- 9% during the low-fat diet and increased by 35 +/- 21% during the high-fat diet (P = 0.014 for liver fat after low- vs. high-fat diets; P = 0.042 for change in liver fat by the low- vs. high-fat diet). Fasting serum insulin averaged 70 +/- 41 pmol/liter at baseline. It decreased to 60 +/- 24 pmol/liter during the low-fat diet (P = 0.007 vs. before low-fat diet) and increased to 81 +/- 44 pmol/liter during the high-fat diet (P = 0.040 vs. before high-fat diet; P = 0.005 for change in serum insulin during low- vs. high-fat diet). Serum lipids, free fatty acids, and intraabdominal and sc fat masses were unchanged. CONCLUSION: These data suggest that the amount of dietary fat influences liver fat content.
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Grasas de la Dieta/administración & dosificación , Metabolismo de los Lípidos , Hígado/metabolismo , Obesidad/metabolismo , Adolescente , Adulto , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Insulina/sangre , Persona de Mediana EdadRESUMEN
We determined whether acquired obesity is associated with increases in liver or intra-abdominal fat or impaired insulin sensitivity by studying monozygotic (MZ) twin pairs discordant and concordant for obesity. We studied nineteen 24- to 27-yr-old MZ twin pairs, with intrapair differences in body weight ranging from 0.1 to 24.7 kg [body mass index (BMI) range 20.0-33.9 kg/m2], identified from a population-based FinnTwin16 sample. Fat distribution was determined by magnetic resonance imaging, percent body fat by dual-energy X-ray absorptiometry, liver fat by proton spectroscopy, insulin sensitivity by measuring the fasting insulin concentration, and whole body insulin sensitivity by the euglycemic insulin clamp technique. Intrapair differences in BMI were significantly correlated with those in intra-abdominal fat (r = 0.82, P < 0.001) and liver fat (r = 0.57, P = 0.010). Intrapair differences in fasting insulin correlated with those in subcutaneous abdominal (r = 0.60, P = 0.008), intra-abdominal (r = 0.75, P = 0.0001) and liver (r = 0.49, P = 0.048) fat. Intrapair differences in whole body insulin sensitivity correlated with those in subcutaneous abdominal (r = -0.72, P = 0.001) and intra-abdominal (r = -0.55, P = 0.015) but not liver (r = -0.20, P = 0.20) fat. We conclude that acquired obesity is associated with increases in intra-abdominal and liver fat and insulin resistance, independent of genetic factors.
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Tejido Adiposo/metabolismo , Hígado Graso/metabolismo , Resistencia a la Insulina/fisiología , Obesidad/metabolismo , Gemelos Monocigóticos/metabolismo , Absorciometría de Fotón , Adulto , Glucemia/metabolismo , Composición Corporal/fisiología , Índice de Masa Corporal , Hígado Graso/genética , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Resistencia a la Insulina/genética , Imagen por Resonancia Magnética , Masculino , Obesidad/genética , Estadísticas no ParamétricasRESUMEN
Microangiopathic end-organ injury is common in type 1 diabetes. However, the pathophysiology of diabetic encephalopathy is poorly understood. The authors studied 10 normotensive patients with type 1 diabetes with retinopathy, autonomic neuropathy, but without nephropathy, and 10 healthy subjects. Proton magnetic resonance spectroscopy was performed at 1.5 T in the frontal cortex, thalamus, and posterior frontal white matter. There was no change in N-acetyl-containing compounds (NA), but choline-containing compounds (Cho) were increased in the white matter and in the thalamus; myo-inositol was increased in the white matter, glucose excess was found in all brain, and water intensity was increased in the cortical voxel in the patients. Calculated lifetime glycemic exposure correlated inversely with Cho and NA in white matter and with Cho in thalamus. Concentrations of soluble intercellular adhesion molecules and vascular cell adhesion molecules were increased in the patients. In conclusion, in patients with type 1 diabetes, the increase in adhesion molecules and an association between altered brain metabolites and glycemic exposure suggest the presence of a vascularly mediated, progressive metabolic disturbance in the brain.
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Lesiones Encefálicas/etiología , Lesiones Encefálicas/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Hiperglucemia/complicaciones , Adulto , Lesiones Encefálicas/patología , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Humanos , Hiperglucemia/metabolismo , Imagen por Resonancia Magnética , MasculinoRESUMEN
The neuronal ceroid lipofuscinoses (NCLs) are among the most severe inherited progressive neurodegenerative disorders of children. The purpose of this study was to compare the in vivo 1.5-T 1H magnetic resonance (MR) and ex vivo 14.3-T high-resolution (HR) magic angle spinning (MAS) 1H MR brain spectra of patients with infantile (CLN1) and juvenile (CLN3) types of NCL, to obtain detailed information about the alterations in the neuronal metabolite profiles in these diseases and to test the suitability of the ex vivo HR MAS (1)H MRS technique in analysis of autopsy brain tissue. Ex vivo spectra from CLN1 autopsy brain tissue (n = 9) significantly differed from those of the control (n = 9) and CLN3 (n = 5) groups, although no differences were found between the CLN3 and the control groups. Principal component analysis of ex vivo data showed that decreased levels of N-acetylaspartate (NAA), gamma-aminobutyric acid (GABA), glutamine, and glutamate as well as increased levels of inositols characterized the CLN1 spectra. Also, the intensity ratio of lipid methylene/methyl protons was decreased in spectra of CLN1 brain tissue compared with CLN3 and control brain tissue. In concordance with the ex vivo data, the in vivo spectra of late-stage patients with CLN1 (n = 3) revealed a dramatic decrease of NAA and a proportional increase of myo-inositol and lipids compared with control subjects. Again, the spectra of patients with CLN3 (n = 13) did not differ from those of controls (n = 15). In conclusion, the ex vivo and in vivo spectroscopic findings were in good agreement within all analyzed groups and revealed significant alterations in metabolite profiles in CLN1 brain tissue but not in CLN3 compared with controls. Furthermore, HR MAS 1H MR spectra facilitated refined detection of neuronal metabolites, including GABA, and composition of lipids in the autopsy brain tissue of NCL patients.
Asunto(s)
Ácido Aspártico/análogos & derivados , Espectroscopía de Resonancia Magnética , Proteínas de la Membrana/metabolismo , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Neuronas/química , Adolescente , Adulto , Análisis de Varianza , Ácido Aspártico/análisis , Encéfalo/anatomía & histología , Encéfalo/patología , Química Encefálica/fisiología , Niño , Preescolar , Colina/análisis , Creatina/análisis , Femenino , Ácido Glutámico/análisis , Glutamina/análisis , Humanos , Inositol/análisis , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Lipofuscinosis Ceroideas Neuronales/clasificación , Neuronas/metabolismo , Tioléster Hidrolasas , Ácido gamma-Aminobutírico/análisisRESUMEN
Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 +/- 3 years, fasting plasma glucose 152 +/- 9 mg/dl, BMI 30.6 +/- 0.8 kg/m2) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA1c, insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 +/- 4 vs. 82 +/- 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 +/- 3 vs. 7 +/- 1%, 0 vs. 16 weeks, P = 0.003) but not by metformin (13 +/- 3 to 14 +/- 3%, NS). Rosiglitazone (16 +/- 2 vs. 20 +/- 1 ml.kg(-1).min(-1), P = 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r = -0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-gamma, adiponectin, and lipoprotein lipase in adipose tissue. In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations. Both agents increase hepatic insulin sensitivity, but only rosiglitazone increases peripheral glucose uptake.
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Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Regulación de la Expresión Génica/genética , Metabolismo de los Lípidos , Hígado/metabolismo , Metformina/farmacología , Tiazolidinedionas/farmacología , Tejido Adiposo/efectos de los fármacos , Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hipoglucemiantes/farmacología , Insulina/sangre , Resistencia a la Insulina/fisiología , Hígado/efectos de los fármacos , Masculino , Persona de Mediana Edad , Rosiglitazona , Triglicéridos/sangreRESUMEN
Both aging and sleep deprivation disturb the functions of the frontal lobes. Deficits in brain energy metabolism have been reported in these conditions. Neurons use not only glucose but also lactate as their energy substrate. The physiological response to elevated neuronal activity is a transient increase in lactate concentrations in the stimulated area. We have previously shown that cognitive stimulation increases brain lactate. To study the effect of prolonged wakefulness on the lactate response we designed an experiment to assess brain lactate levels during a 40-h sleep deprivation period in young (19-24 years old; n = 13) and in aged (60-68 years old; n = 12) healthy female volunteers. Brain lactate levels were assessed with proton MR-spectroscopy ((1)H MRS) during the performance of a silent word generation task. The (1)H MRS voxel location was individually selected, using functional magnetic resonance imaging, to cover the activated area in the left frontal lobe. The degree of sleepiness was verified using vigilance tests and self-rating scales. In the young alert subjects, the silent word generation test induced a 40% increase in lactate, but during the prolonged wakefulness period this response disappeared. In the aged subjects, the lactate response could not be detected even in the alert state. We propose that the absence of the lactate response may be a sign of malfunctioning of normal brain energy metabolism. The behavioral effects of prolonged wakefulness and aging may arise from this dysfunction.
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Envejecimiento/fisiología , Encéfalo/metabolismo , Cognición/fisiología , Ácido Láctico/metabolismo , Vigilia/fisiología , Adulto , Factores de Edad , Anciano , Encéfalo/anatomía & histología , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Persona de Mediana Edad , Conducta Verbal , VocabularioRESUMEN
PURPOSE: To assess proton magnetic resonance (MR) spectroscopy in differentiating between low-grade gliomas and focal cortical developmental malformations (FCDMs). MATERIALS AND METHODS: Eighteen patients with seizures and a cortical brain lesion on MR images were studied with proton MR spectroscopy. A metabolite ratio analysis was performed, and the metabolite signals in the lesion core were compared with those in the contralateral centrum semiovale and in the corresponding brain sites in 18 control subjects to separately obtain the changes in N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine-phosphocreatine (Cr). Ten patients had a low-grade glioma (three, oligodendrogliomas; three, oligoastrocytomas; three, astrocytomas; and one, pilocytic astrocytoma), and eight had FCDM (five, focal cortical dysplasias and three, dysembryoplastic neuroepithelial tumors). Linear discriminant analysis and Student t test were used for statistical comparisons. RESULTS: Loss of NAA and increase of Cho were more pronounced in low-grade gliomas than in FCDMs (NAA, -72% +/- 15 [+/- SD] vs -29% +/- 22, P <.001; Cho, 117% +/- 56 vs 21% +/- 66, P <.01). Changes in NAA and Cho helped differentiate low-grade gliomas from FCDMs, and changes in Cho and Cr helped differentiate astrocytomas from oligodendrogliomas and oligoastrocytomas. Metabolite NAA/Cho and NAA/Cr ratios helped differentiate low-grade gliomas from FCDMs but did not differentiate glioma subtypes. CONCLUSION: MR spectroscopy allows distinction between low-grade gliomas and FCDMs and between low-grade glioma subtypes. Metabolite changes are more informative than are metabolite ratios.
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Ácido Aspártico/análogos & derivados , Astrocitoma/diagnóstico , Corteza Cerebral/anomalías , Espectroscopía de Resonancia Magnética , Tumores Neuroectodérmicos Primitivos/diagnóstico , Oligodendroglioma/diagnóstico , Adolescente , Adulto , Ácido Aspártico/análisis , Corteza Cerebral/patología , Niño , Colina/análisis , Creatina/análisis , Diagnóstico Diferencial , Epilepsias Parciales/diagnóstico , Epilepsias Parciales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfocreatina/análisis , Sensibilidad y EspecificidadRESUMEN
In Cushing's syndrome, cortisol causes fat accumulation in specific sites most likely to be associated with insulin resistance, notably in omental adipose and also perhaps in the liver. In idiopathic obesity, cortisol-metabolizing enzymes may play a key role in determining body fat distribution. Increased regeneration of cortisol from cortisone within adipose by 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11HSD1) has been proposed to cause visceral fat accumulation, whereas decreased hepatic 11HSD1 may protect the liver from glucocorticoid excess. Increased inactivation of cortisol by 5alpha- and 5beta-reductases in the liver may drive compensatory activation of the hypothalamic-pituitary-adrenal axis, hence increasing adrenal androgens and 'android' central obesity. This study aimed to examine relationships between these enzymes and detailed measurements of body fat distribution. Twenty-five healthy men (age, 22-57 yr; body mass index, 20.6-35.6 kg/m(2)) were recruited from occupational health services. Body composition was assessed by anthropometric measurements, bioimpedance, and cross-sectional abdominal magnetic resonance imaging scans. Liver fat content was assessed by magnetic resonance imaging spectroscopy. Insulin sensitivity was measured in a euglycemic hyperinsulinemic clamp. Cortisol metabolites were measured in a 24-h urine sample by gas chromatography-mass spectrometry. In vivo hepatic 11HSD1 activity was measured by generation of plasma cortisol after an oral dose of cortisone. In vitro 11HSD1 activity and mRNA were measured in 18 subjects who consented to provide abdominal sc adipose biopsies. Indices of obesity (body mass index, whole-body percentage fat, waist/hip ratio) were associated with higher urinary excretion of 5alpha- and 5beta-reduced cortisol metabolites (for percentage fat, P < 0.05 and P < 0.01, respectively) and increased adipose 11HSD1 activity (P < 0.05). Liver fat accumulation was associated with a selective increase in urinary excretion of 5beta-reduced cortisol and cortisone metabolites (P < 0.01) and a lower ratio of cortisol/cortisone metabolites in urine (P < 0.001) but no difference in in vivo cortisone-to-cortisol conversion or in vitro adipose 11HSD1. Higher excretion of 5beta-reduced cortisol metabolites was independently associated with insulin resistance and hypertriglyceridemia. Lower conversion of cortisone to cortisol was associated with lower fasting plasma cortisol (P < 0.01). However, visceral adipose fat mass was not associated with indices of cortisol metabolism; indeed, after adjusting for the effects of whole-body and liver fat, increased visceral fat was associated with lower cortisol metabolite excretion. We conclude that alterations in 11HSD1 and hepatic 5alpha-reductase activity are associated with generalized, rather than central, obesity in humans. Activation of 5beta-reductase in men with fat accumulation in the liver may confound the interpretation of cortisol metabolite excretion when liver fat content is unknown, and may contribute to altered bile acid and cholesterol metabolism in nonalcoholic steatohepatitis.
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Tejido Adiposo/metabolismo , Composición Corporal , Cortisona/metabolismo , Hígado Graso/metabolismo , Hidrocortisona/metabolismo , Oxidorreductasas/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1 , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Adulto , Hígado Graso/patología , Humanos , Hidroxiesteroide Deshidrogenasas/metabolismo , Hígado/enzimología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Análisis de RegresiónRESUMEN
RATIONALE AND OBJECTIVES: To evaluate liver and liver tumor perfusions by using two different modelling methods: gamma-variate fitting and a single-compartment model. MATERIALS AND METHODS: 5 New Zealand White rabbits with VX2 tumor implanted into the liver via portal injections were studied. Contrast-enhanced functional CT (fCT) examinations with temporal resolution of 200-500 milliseconds were conducted before tumor inoculation. Thereafter, two or three follow-up studies were conducted. A gamma-variate fitting method was used to determine fractional blood volumes (BV), and a single-compartment model method was used to determine fractional blood volumes (BV), blood flows (BF), and mean transit times (MTT) for normal and tumorous liver regions. RESULTS: For tumorous regions in liver, the gamma-variate fitting and the single-compartment model methods showed statistically significant increases in arterial perfusions (P < 0.01) and decreases in portal perfusions (P < 0.01 with single-compartment model, and P < 0.05 with gamma-variate fitting) when compared with normal liver regions. The single-compartment model showed statistically significant increases (P < 0.01) in MTTs in tumorous regions. In normal liver regions, portal BFs decreased and MTTs increased after tumor inoculation, but the changes were statistically not significant. CONCLUSION: The gamma-variate fitting and the single-compartment model methods showed definite differences in perfusions between normal and tumorous regions in liver. The single-compartment model showed slightly more distinction and was faster. More importantly, both methods can easily be applied in the clinical environment in the assessment of liver perfusion.
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Neoplasias Hepáticas Experimentales/irrigación sanguínea , Tomografía Computarizada por Rayos X/métodos , Algoritmos , Animales , Medios de Contraste , Hígado/irrigación sanguínea , Perfusión , Sistema Porta/fisiología , ConejosRESUMEN
Proton magnetic resonance spectroscopy (1H-MRS) allows in vivo assessment of the metabolism related to human brain functions. Visual, auditory, tactile, and motor stimuli induce a temporary increase in the brain lactate level, which may act as a rapid source of energy for the activated neurons. The authors studied the metabolism of the frontal lobes during cognitive stimulation and measured local lactate levels with standard 1H-MRS, after localizing the activated area by functional MRI. Lactate levels were monitored while the subjects either silently listed numbers (baseline) or performed a silent word-generation task (stimulus-activation). The cognitive stimulus-activation produced a 50% increase in the brain lactate level in the left inferior frontal gyrus. The results show that metabolic imaging of neuronal activity related to cognition is possible using 1H-MRS.
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Encéfalo/fisiología , Cognición/fisiología , Ácido Láctico/metabolismo , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Adulto , Encéfalo/metabolismo , Femenino , Humanos , Habla/fisiologíaRESUMEN
Highly active antiretroviral therapy (HAART) is associated with metabolic adverse events such as insulin resistance and lipodystrophy, that is, atrophy of subcutaneous fat and accumulation of intra-abdominal fat. Currently, there is no pharmacological treatment for lipoatrophy. Glitazones, a novel class of insulin-sensitizing anti-diabetic agents, increase subcutaneous fat in patients with type 2 diabetes. There are no controlled studies of glitazones in patients with HAART-associated lipodystrophy (HAL). In this randomized, double-blind, placebo-controlled study, 30 patients with HAL received either rosiglitazone (8 mg daily) or placebo for 24 weeks. Baseline characteristics were compared to a group of 30 age-, sex- and weight-matched HIV-negative controls. At baseline, patients with HAL had 1.8-fold (P<0.001) more intra-abdominal and 2.4-fold (P<0.05) more liver fat than HIV-negative controls, who had 1.8-fold (P<0.001) more subcutaneous fat than the patients. After 24 weeks of treatment, rosiglitazone had no effect on body weight, subcutaneous or intra-abdominal fat (magnetic resonance imaging), total body fat (bioimpedance analysis), anthropometric measurements or serum leptin concentrations (a circulating marker of adipose tissue mass). However, rosiglitazone decreased % liver fat (spectroscopy) and serum insulin concentrations, and normalized liver function tests. During the first 12 weeks of rosiglitazone treatment, serum triglycerides increased from 3.5 +/- 0.5 to 6.5 +/- 2.0 mmol/l (from 310 +/- 44 to 575 +/- 177 mg/dl) (P<0.05) and serum cholesterol from 6.0 +/- 0.4 to 7.8 +/- 0.7 mmol/l (from 232 +/- 15 to 301 +/- 27 mg/dl) (P<0.01). Contrary to data in other patient groups, rosiglitazone did not increase subcutaneous fat in patients with HAL after 24 weeks of treatment. Rosiglitazone seemed to ameliorate insulin resistance judged by the decreased serum insulin concentrations and % liver fat. Rosiglitazone unexpectedly caused significant increases in serum triglyceride and cholesterol concentrations, which must be carefully monitored if glitazones are used in these patients.